The overall goals of this grant application are to 1) develop an effective chemoprevention strategy to reduce the risk of bladder cancer recurrence and to 2) investigate surrogate biomarkers that can serve as intermediate endpoints of the interventional efficacy of chemoprevention. Bladder cancer represents an important health problem in the United States and it currently ranks as the fourth most common cancer site in men and the eight most leading site in women. Since these tumors have a very high incidence of recurrence, the psychological and economic burden to the health care system of repeated diagnostic evaluations and therapy are substantial. Bladder cancer is an ideal model for studies of risk assessment early detection, chemoprevention and the development of intermediate biomarkers. Cigarette smoking represents the single most significant, preventable cause of bladder cancer and its carcinogenesis has a long latency period of close to twenty years following initial exposure, providing ample opportunities for intervention. Recently several potential surrogate end point markers have been developed for the detection of the clinically occult, premalignant phase of bladder cancer. These markers include the QFIA biomarker profile (DNA/M344/Actin Associated Protein) urinary basic fibroblast growth factor (bFGF) measurement, and Microsatellite Instability (MI) markers. Using the tumor recurrence rate as a primary end point and the biomarkers as secondary end points, we propose to perform a randomized, placebo-controlled, clinical trial using two promising chemoprevention agents targeting specific biochemical pathways on a cohort of high risk individuals who are former smokers with a grater than 30 pack year smoking history. Eligible subjects will have had a previous episode of low grade, low stage cancer of the bladder who are at high risk to develop disease recurrence, but for whom the standard of care would be observation. We will also construct tissue microarrays using specimens obtained during the evaluation of this clinical cohort to perform present and future translational high throughput studies to study the expression of markers associated with genetic susceptibility and tumor progression, and to identify potential therapeutic targets for cancer prevention. This grant application will involve a multi-disciplinary approached based on organization into program cores. An Administrative Core will perform the overall oversight for all aspects of the proposed work. A Clinical Core will run the clinical trial. The development and evaluation of the proposed biomarkers will be performed by the Biomarker and Nutritional Cores. All tissue samples will be collected and stored, and tissue arrays constructed by the Tissue Core. Finally, the Biostatistics Core will help design the clinical trial and evaluate the measured endpoints.